Pyridine Elaboration through Organometallic

Intermediates: Regiochemical Control and Completeness

Manfred Schlosser, Florence Mongin

To cite this version:

Manfred Schlosser, Florence Mongin. Pyridine Elaboration through Organometallic Interme-diates: Regiochemical Control and Completeness. Chemical Society Reviews, Royal Society ofChemistry, 2007, 36, pp.1161-1172. <10.1039/b706241a>. <hal-01002816>

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1

Pyridine Elaboration through Organometallic

Intermediates: Regiochemical Control and Completeness

Manfred Schlosser *[a] and Florence Mongin [b]

Pyridines carrying heterosubstituents (such as carboxy, amido, amino, alkoxy or

trifluoromethyl groups or solely individual halogen atoms) can be readily and site selectively

metalated. Subsequent reaction with a suitable electrophile opens rational access to a wealth

of new building blocks for the synthesis of biologically active compounds. This approach

relies on organometallic methods, which are both efficacious and extremely flexible as far as

the substitution site and the product structure are concerned.

Key Words: Pyridine • Metalation • Heterosubstituents • Electrophiles • Lithium

Compounds • Superbase Chemistry

1. Introduction

Pyridines belong to the most prominent and most important heterocycles. Derivatives

such as nicotine, nicotinamide (niacin) and nicotinamide adenine dinucleotide diphosphate

(NADP) or pyridoxine (vitamin B6) occupy biological key positions. In addition, countless

pyridine congeners are registered as pharmaceutically or agriculturally active principles. In

general, a fair degree of structural complexity characterizes such compounds. This calls for

highly selective, flexible and efficacious methods of synthesis.

_________________________________________

[a] Institute of Chemical Sciences and Engineering (ISIC) Ecole Polytechnique Fédérale, BCh CH-1015 Lausanne, Switzerland

e-mail : manfred.schlosser@epfl.ch fax: ++41-21-6939365 [b] Synthèse et Electrosynthèse organiques Université de Rennes 1, CNRS Bâtiment 10A, Case 1003, Campus scientifique de Beaulieu F-35042 Rennes, France

e-mail : florence.mongin@univ-rennes1.fr fax : +33-2-23-23-69-55

2

Pyridine itself can be extracted from coal tar or made by condensation of crotonaldehyde

and formaldehyde with ammonia in the presence of air.[1] It undergoes electrophilic

substitutions such as nitration, sulfonation and halogenation exclusively at the 3-position.[1] 3-

Bromopyridine can be converted into 3-acetonylpyridine by a single electron-transfer

mediated reaction with the potassium enolate of acetone in liquid ammonia and into 3-

aminopyridine using ammonia in the presence of copper sulfate at elevated temperatures.[1]

Halogen atoms located at the 2- or 4-position are readily displaced by all kinds of

nucleophiles under mild conditions and without requiring transition element assistance.[1]

Pyridine reacts with sodium or potassium amide to afford 2-aminopyridine (Tchitchibabin

process) and with organometallics such as butyllithium or phenyllithium to give the

corresponding 2-alkyl- or 2-arylpyridine after metal hydride elimination or direct

oxidation.[1,2] In contrast, Grignard reagents add at the position of N-silylated pyridines.[3]

There is a trick to reorient electrophilic substitution from the ordinary 3-position also to

the 4-position. As long as unprotonated, pyridine N-oxides accommodate the reagent cleanly

at the N-remote site.[4] Catalytic hydrogenation smoothly reduces the resulting 4-nitropyridine

N-oxide to 4-aminopyridine.[5] The same conditions can be applied to convert 3-nitropyridine

to 3-aminopyridine. Conversely, 2-nitropyridine is prepared from the directly accessible 2-

aminopyridine by treatment with peroxosulfuric acid.[6] All three aminopyridines (Scheme 1)

can be further transformed in many ways, in particular through to corresponding diazonium

salts.

N

O

N

O

NO2

N

NH2

N N N

NO2 NH2

N N NH2NO2

Scheme 1. The three aminopyridines derived directly or indirectly from the parent compounds.

Problems arise as soon as a second substituent has to be attached to the pyridine nucleus.

Regioisomeric mixtures will be obtained almost inevitably. Sometimes the selectivity is still

amazingly high. For example, 3-methoxypyridine provides a 10 : 1 mixture of 2- and 6-

nitration products and no 4- or 5-isomers at all (Scheme 2).[7] More typically, however,

product mixtures result that are worthless in practical terms. Thus, 2-aminopyridine gives rise

3

to half a dozen of mono-, di- and tribrominated derivatives when treated with elemental

bromine in solution or in the gas phase (Scheme 3).[8]

N

OCH3

2

4

5

6

N

OCH3

N

OCH3

N

OCH3

N

OCH3

O2N

NO2

NO2 O2N

Scheme 2. The not perfectly regioselective nitration of 3-methoxypyridine.

N

NN NH2

NH2

N NH2 NH2

Br

Br

Br

NN NH2 N NH2 NH2

BrBr

Br

Br Br

Br

N NH2

Br Br

Br

major

major

major

Scheme 3. Mono-, di- and tribrominated derivatives formed upon bromination of 2-aminopyridine.

Site selectivity could be easily achieved of course if the electrophile would be allowed to

react with a specific metal-bearing pyridine rather than with the unmodified heterocycle

having several vacant and hence potentially eligible positions. Pyridylmagnesium halides

(Scheme 4) and pyridyllithiums (Scheme 4) are readily generated by the reductive insertion of

a metal (such as magnesium)[9] into the carbon-halogen bond of a given bromopyridine or by

permutational halogen/metal interconversion of the latter with isopropylmagnesium

chloride[10] or butyllithium.[11] Dibromopyridines could serve as particularly attractive starting

materials as they offer the possibility to replace one halogen by a first electrophile and the

other one by a second electrophile. Unfortunately, this approach suffers from serious

drawbacks. First of all, halogens of the same kind can be alternatively and selectively

exchanged against metal only in exceptional cases, so far just in 2,5-dibromopyridine and

2,3,5-tribromopyridine (Scheme 4).[12] Ordinarily, the two halogen atoms (as present, e.g., in

4

3,4-dibromopyridine) are attacked randomly. Moreover, the use of dibromopyridines as key

starting materials would only defer the problem as their regioselective preparation is in

general not trivial. Finally, unexpected complications may be encountered. Thus, the

exchange by-product 1-bromobutane may react, even unnoticed by the authors,[13] with the

newly generated organometallic intermediate.

NN M N

M

M

NN M N N

Br

Br

M

M

BrBr

Br

MBr

[M = MgCl(Br), Li]

Scheme 4. Site specifically activated pyridines by bromine/magnesium or bromine/lithium exchange (reductive insertion or permutational interconversion): 2-, 3- and 4-pyridylmetals and bromopyridylmetals.

The lesson to be drawn from this dilemna is simple: maintain the organometallic route as

a guiding principle for the electrophilic substitution of heterocycles but introduce the metal by

metalation (i.e., hydrogen/metal permutation) rather than by halogen/metal exchange (be it

insertion or permutation). The metalation and subsequent substitution, in particular

functionalization of a variety of pyridines will be extensively reviewed in the following

Sections. To resume already now, the metalation of pyridine itself or its alkyl- or aryl-bearing

congeners is not very tempting under a synthesis point of view but is a highly appealing

option if the metalation is assisted and oriented by electronegative substituents.

2. Metalation

2.1 Pyridine and Picolines

Brandsma et al.[14] have reported the metalation of pyridine using our superbasic LIC-

KOR[15,16] mixture (LIC = butyllithium, plus KOR = potassium tert-butoxide) as the reagent.

The observed blue color, the moderate yields and notably the found product composition of

2-, 3- and 4-isomers raise doubts about the assumed deprotonation process and argue rather

for a single electron-transfer (SET) mechanism. The latter is definitively operative when

pyridine is treated by lithium diisopropylamide (LIDA) in diethyl ether (DEE) and in the

presence of hexamethylphosphoric triamide (HMPT) as evidenced by the formation of 2,2'-

bipyridine in 50% yield.[17] On the other hand, deprotonation can be brought about when

5

facilitated by coordinative neighboring group assistance. When treated, under in situ trapping

conditions, simultaneously with lithium 2,2,6,6-tetramethylpiperidide (LITMP) and

tributylchlorostannane in tetrahydrofuran (THF), 2,2'-bipyridyl gives via the intermediates 1

and 2 the mono-3- and di-3,3'-stannylated derivatives in 50% and 14% yield, respectively. In

the same way, 2,4'-bipyridyl can be converted via the species 3 into the 2'-stannane in 64%

yield (Scheme 5).[18]

NN

NN

NN

NN

NN

N

N

N

N

N

N

3

3'

3

3'

[a] [b]Li Sn(C4H9)3

1

[a]

2

Li

Li

[b]Sn(C4H9)3

[a] [b]

3Li (H9C4)3Sn

(H9C4)3Sn

Scheme 5. Deprotonation of 2,2'- and 2,4'-bipyridyl with LITMP and in situ trapping of the intermediates 1 – 3 with tributylchlorostannane. Reaction conditions: [a] LITMP in THF at –70 °C and in the presence of [b] tributylchlorostannane.

Coordination of lithium to the ring nitrogen atom is without doubt also at the origin of the

remarkable selectivity of Caubère's base,[19] the 1 : 1 mixture of butyllithium with lithium 2-

(dimethylamino)ethoxide (LIDMAE), toward pyridines. To favor complexation, the reaction

is generally conducted in hexanes, but also DEE and THF can be employed. Pyridine,[19c] 4-

methylpyridine (-picoline) and 3,5-dimethylpyridine (,'-lutidine)[19f] are metalated

exclusively at the 2-position generating intermediates 4 (Scheme 6).

N N N

[a] [b]

4

R R

Li

R

El

[R = H, CH3]

Scheme 6. Selective metalation of pyridine and 4-methylpyridine using Caubère's base. Reaction conditions: [a] LiC4H9 + LiOCH2CH2N(CH3)2. [b] El-X = ICH3, ClSi(CH3)3, H3CS-SCH3, H5C6-CH=O, (H2C)5C=O, (H3C)2N-CH=O, etc.

Despite this impressive record, Caubère's base does nevertheless not always behave

regioselectively. For example, 3,4-dimethylpyridine (,-lutidine) undergoes lithiation

6

concomitantly at the 2- and 6-position and at the 4-methyl group as well (in a 78 : 5 : 17

ratio).[19h] Moreover, the reagent has to be used in large excess (3- to 20-fold) which

inevitably consumes large amounts of the electrophile and limits the scale (to 1 – 5 mmol of

substrate in most cases). Under such circumstances alternative possibilities should be kept in

mind. They are briefly outlined in the next Section.

2.2 Pyridine Oxides and Pyridine Borates

As a systematic investigation has revealed,[20] pyridine N-oxides are selectively metalated

at the 2-position (intermediates 5, Scheme 7). Unfortunately the yields are poor (14 - 44%).

Disubstituted derivatives rank among the most abundant by-products.

N N N

[a] [b]

5

Li El

[R = H, 2-, 3- and 4-H3C, 4-H3CO, 4-Cl]

R

O O O

R R

Scheme 7. Metalation of pyridine N-oxides. Reaction conditions: [a] LiC4H9 (in DEE or THF); [b] El-X = CO2, (H5C6)2C=O, (H2C)5C=O.

-Oxidopyridinium betaines also are amenable to lithiation at the 2-position

(intermediates 6, Scheme 8).[21] The zwitterionic substrates form readily when the pyridine

and hexafluoroacetone are combined.

N N N

[a] [b]

6

Li El

[R = H, C(CH3)3]

R R R

CF3F3C

OCF3

F3CO

Scheme 8. Metalation of pyridine/hexa-fluoroacetone adducts. Reaction conditions: [a] LITMP in THF at –107 °C; [b] El-X = H5C6-CH=O, (F3C)2C=O, I2, ClSi(CH3)3.

Intermediates 5 and 6 suggest a coordinative interaction between the oxido anion and

lithium. However, mere electrostatic effects suffice to activate the 2-position toward proton

abstraction accomplished with strong bases as evidenced by the behavior of pyridine,[22] 4-

methylpyridine[22] and 4-(dimethylamino)pyridine[23] adducts with boron trifluoride

(intermediates 7, Scheme 9).

7

N N N

[a] [b]

7

Li El

[R = H, CH3, N(CH3)2]

BF3 BF3

R R R

Scheme 9. Metalation of pyridine/boron trifluoride adducts. Reaction conditions: [a] LITMP in DEE at –75 °C; [b] El-X = H5C6-CH=O, (H5C6)2C=O, (CH2)5C=O.

The potential of the latter method is far from being explored and exploited. In the absence

of boron trifluoride, -picoline is deprotonated at the methyl group. The scope of lithium di-

tert-butyl-2,2,6,6-tetramethylpiperid-1-ylzincate for the lithiation of heterocycles at N-

adjacent sites, so far demonstrated with pyridine, quinoline and isoquinoline on a quasi-

analytical 1.0 mmol scale[24] deserves to be tested further.

2.3 Pyridinecarboxylic Acids and Congeners

Both ethyl pyridine-3- and -4-carboxylate were found to be very prone to proton

abstraction by lithium diisopropylamine at the 4- and 2-position, respectively. However, the

lithiated species proved unstable, being lost by instantaneous autocondensation.[25] Such

problems can be circumvented when pyridinecarboxylic acids themselves or halogenated

derivatives thereof are treated with two molar equivalents of LITMP in THF at –75 °C or –50

°C.[26] The thus generated intermediates 8 and 9 (Scheme 10) can be effectively trapped by a

variety of electrophiles.

N N N

8a 8b 8c

N N N

9a 9b 9c

COOLi

Li COOLi

Li

Li

COOLi

COOLi

Li

BrCOOLi

Li

ClCl

COOLi

Li

Scheme 10. Organolithium species generated by treatment of pyridine-2-, -3- and -4-carboxylic acid, 2- and 6-chloropyridine-3-carboxylic acid and 5-bromopyridine-3-carboxylic acid with LITMP (2 equiv.).

8

Abstraction of a "mobile proton", this time from an NH entity, precedes also the

neighboring group assisted metalation of secondary pyridinecarboxamides (e.g., intermediates

10 and 11, Scheme 11)[27] which occurs analogously as established in the benzene series.[28]

NN

N

10 11a 11b

Li

CLi

OCH3

C=N-CH2C6H5

Li

LiO OCH3

C=N-C6H5

LiO

N-C6H5LiO

Scheme 11. 3-Lithiated N-benzyl or N-phenyl pyridinecarboxamides.

Although in the benzene series sec-butyllithium is required,[29] tertiary

pyridinecarboxamides undergo smooth deprotonation at a vacant 3- or 4-position even with

LIDA as the base (intermediates 12 and 13, Scheme 12).[30] The N-substituents are generally

isopropyl groups but also ethyl groups are appropriate.

N N N

12a 12b 12c: X = H13: X = OCH3

Li

C

C

Li

C=O

Li

X

NR2O

[R = CH(CH3)2, C2H5]

NR2

O

R2N

Scheme 12. 3- or 4-Lithiated N,N-diisopropyl (or N,N-diethyl) pyridine-2-, -3- or -4-carboxamides.

Oxazolines are imino-ethers incorporated into a ring structure and hence are masked

carboxylic acids, which are immediately formed upon acidic hydrolysis. Following precedents

encountered in the benzene[31a] and thiophene series,[31b] 3- and 4-(4,5-dihydro-4,4-

dimethyloxazol-2-yl)pyridines are readily metalated at the 4- and 3-position, respectively

(intermediates 13 and 14, Scheme 13).[32] It is advisable to employ relatively weak bases such

as methyllithium or LITMP as most organomagnesiums or organolithiums tend to add

nucleophilically to the 4-position.

N N

13a 13b: X = H14: X = OCH3

Li

Li

X

O

NNO

Scheme 13. 4- or 3-Lithiated 3- and 4-(4,5-dihydro-4,4-dimethyloxazol-2-yl)pyridines.

9

2.4 Amino- and Amido-Substituted Pyridines

Guided once more by leads existing in the benzene series,[33] N-pivaloyl[34] or N-tert-

butoxycarbonyl[35] protected 2-, 3- and 4-aminopyridines have been effectively metalated

using butyllithium or tert-butyllithium (intermediates 15 – 18, Scheme 14). The

organometallic species produced in this way open an easy access to a variety of valuable,

biologically active compounds.

NN N

15a: R = C(CH3)3

16a: R = OC(CH3)3

15b: R = C(CH3)3

16b: R = OC(CH3)3

15c: R = C(CH3)3

16c: R = OC(CH3)3

N N

17 18

N=C

LiN=C

Li

Li

N

N=C

Li

N=C

Li

OLi

R X

OLi

R

C

R

OLi

OLi

CH2(CH3)3

H3CO

OCH3H3C

OLi

OCH2(CH3)3

Scheme 14. 3- or 4-Lithiated N-pivaloyl or N-tert-butoxycarbonyl protected 2-, 3- and 4-aminopyridines.

The metalation of (N,N-dialkylamino)alkyl substituted pyridines has been only scarcely

examined up to now. Both 2- and 4-(dimethylamino)pyridine[19g] and 3-(N-methylpyrrolidin-

2-yl)pyridine (nicotine)[36a] were found to be attacked by an excess of Caubère's base in

hexanes exclusively at the 6-position, whereas lithiation of 6-chloronicotine with butyllithium

occurred cleanly at the 5-position[36b] (intermediates 19 and 20, Scheme 15).

N N

19 20

ClLi

NLi

N

Scheme 15. Metalation of nicotine and 6-chloronicotine at the 6- and 5-position, respectively.

2.5 Hydroxy- and Alkoxy-Substituted Pyridines

Methoxypyridines and other alkoxypyridines are readily metalated by lithium

dialkylamides such as LIDA or LTMP and by aryllithiums such as mesityllithium or

phenyllithium (intermediates 21 – 24, Scheme 16).[37] Caubère's base promotes the metalation

10

of 4-methoxypyridine at the 3-position.[19g] Neat alkyllithiums, in particular butyllithium, tend

to add nucleophilically at the 2- or 6-position, a sometimes quantitative process.[19b,37b,38]

N NN

21a: X = H22 : X = H3CO

21b 21c

N N

23 24

OR

Li ORLi

OR

OCH2OCH3

Li

X Li

OCH3Li

[OR = OCH3, OC2H5, OCH2C6H5]

Scheme 16. Lithiated alkoxypyridines.

Two remarkable optional site selectivities deserve attention. As mentioned in the

preceding paragraph, 2-methoxypyridine is attacked by lithium amides or aryllithiums

exclusively at the 3-position,[37a,b,e] but by Caubère's base solely at the 6-position.[19c] 3-

Ethoxy and 3-methoxypyridine get deprotonated, respectively, by LIDA and by Caubère's

base[19g] at the 2-position[37a] whereas 3-(methoxymethoxy)pyridine reacts at the more acidic

4-position.[39]

O-Lithiated hemiaminals can be easily formed by nucleophilic addition of either an

organolithium to a dialkylformamide or of a lithium dialkylamide to a carbaldehyde. As first

demonstrated by H.W. Gschwend et al.,[40] the lithium -dialkylaminomethoxide unit

provides neighboring group assistance to the metalation of adjacent aromatic positions. In the

intramolecular competition with a methoxy group, the chelating N-(2-dimethylaminoethyl)-N-

methylamino chain proves to be a superior and the less flexible N'-methyl-N-piperidazyl ring

an inferior ortho-directing substituent. They give rise to the intermediates 24a and 24b,

respectively (Scheme 17).[41]

N N

Li

N

OLi

N

OLi

H3CO H3CO

Li

24a 24b

N

N

Scheme 17. C-Lithiated lithium -(6-methoxy-pyridyl)--(dialkylaminomethoxides.

2.6 Halo- and Trifluoromethyl-Substituted Pyridines

The metalation of halopyridines was pioneered by G. W. Gribble et al.[42] Using LIDA as

the base, 2-bromopyrid-3-yllithium,[43b] 3-bromopyrid-4-yllithium,[42,43a] 4-bromopyrid-4-

11

yllithium [43c] and 3,5-dibromopyrid-4-yllithium[44] have been made accessible. All these

intermediates (25 – 26, Scheme 18) are fairly stable in THF at –100 °C.

N N N

25a 25b 25c

N

26

Br

Li Br Li

Br

Br

Li

Li

Br

Scheme 18. Lithiated bromopyridines.

Some of the reported regiohomogenities have to be met with caution, however. As a

careful reexamination has revealed,[45] species 25a is contaminated by the isomeric 2-

bromopyrid-4-yllithium in an approximate 9 : 1 ratio. Traces of 3-bromopyrid-2-yllithium are

still produced at –100 °C along with 3-bromopyrid-4-yllithium and the amount of undesired

compounds increases at higher temperatures.

2-Chloropyrid-3-yllithium (27a), 3-chloropyrid-4-yllithium (27c) and 4-chloropyrid-3-

yllithium (27d) are readily generated when the corresponding chloropyridines are treated with

LIDA [42] (Scheme 19). In contrast, when butyllithium in the presence of N,N,N',N'-

tetramethylethylenediamine (TMEDA)[43a] or Caubère's base[46] is employed, 3-chloropyridine

gives, respectively, mainly or exclusively 3-chloropyrid-2-yllithium (27b). 4-Chloropyridine

undergoes lithiation at the 2-position (intermediate 27e) when Caubère's base is employed in

hexane at –75 °C.[19g]

N N N

27a 27b 27c

Cl

Li Cl Cl

Li

N

27d

Li

Cl

N

27e

Cl

Li Li

Scheme 19. Lithiated monochloropyridines.

Optional site selectivity[12,47] of metalation is characteristic for several dichloropyridines.

Whatever the base, 2,3-,[48] 2,4-[49] and 3,5-[50]dichloropyridine are only deprotonated at the 3-

and 4- position (intermediates 28, Scheme 20).

N N N

28a 28b 28c

Cl

Cl Li Cl

Li

Cl

Li Cl

Cl

12

Scheme 20. Site-immutable metalation of three dichloropyridines.

However, 2,6-dichloropyridine affords 2,6-dichloropyrid-3-yllithium (29a) and 2,6-

dichloropyrid-4-yllithium (29b) in a 10 : 1 or 1 : 3 ratio depending on whether LIDA or

butyllithium serves as the base[51] (Scheme 21). 2,5-Dichloropyridine reacts cleanly with tert-

butyllithium at the 6-position and with the butyllithium/TMEDA complex at the 4-position

(intermediates 30, Scheme 20). 3,4-Dichloropyridine undergoes selective metalation with

LITMP in DEE at the 2-position and with LIDA in THF at the 5-position (intermediates 31,

Scheme 21).

N N N

29a 29b

Cl

Li

Li

Cl

N N NLi

Cl Cl Cl

Li

N N NLi

Cl Cl Cl

ClCl Cl

Li

30a 30b

31a 31b

Cl Cl ClCl

ClClCl

Scheme 21. Optional site selectivity in the metalation of 2,6-, 2,5- and 3,4-dichloropyridine.

Low temperature protocols should equally enable the generation and subsequent

transformation of tri- and tetrachloropyridyllithiums. The only example of that kind known so

far is 2,3,6-trichloropyrid-4-yllithium.[52]

2-Fluoropyridine[42,53] and 4-fluoropyridine[54] are readily metalated at the 3-position

(intermediates 32a and 32d, Scheme 22). Deprotonation of 3-fluoropyridine[55] occurs cleanly

at the most acidic 4-position after long exposure times and in relative basic media whereas the

2-position is favored when neighboring group assistance by coordination to the ring nitrogen

atom is effective. Thus, TMEDA-activated butyllithium metalates 3-fluoropyridine solely at

the 4-position when applied in THF, but mainly at the 2-position when in DEE[55]

(intermediates 32c and 32b, respectively, Scheme 22). When TMEDA is replaced by the non-

chelating 1,8-diazabicyclo[2.2.2]octane (DABCO), the 2-position is exclusively attacked in

DEE.[55c]

13

N N N

32a 32b 32c

F

Li F F

Li

N

32d

Li

F

Li

Scheme 22. Selective metalation of 2-, 3- and 4-fluoropyridine.

2-Fluoropyridine has four different vacant positions. To illustrate the concept of

"regiochemically exhaustive substitution",[12, 56] the carboxy group was introduced into each

of these empty sites passing through the organometallic intermediates 32a and 33a – 33c[57]

(Scheme 23). The execution relies on our "toolbox methods"[12] and, more precisely, the

clever use of two favorite protective groups. Bulky trialkylsilyl entities do not only impede

the access of any reagent to the site they occupy themselves but also screen sterically the

directly adjacent positions. Thus, 3-chloro-2-fluoro-4-(trimethylsilyl)pyridine can only be

deprotonated at the 6-position . In contrast, the protective chlorine substituent eliminates the

3-position as an acidic site but, at the same time, activates the adjacent 4-position. In this way,

a trimethylsilyl group or a second chlorine atom can be readily introduced there to deflect the

metalation to the 6- and 5-position, respectively.[57] After quenching of the intermediates with

the desired electrophile, the protective groups can be conveniently removed by

protodesilylation or reduction (Scheme 23).

N N N

33a 32a 33b

F

Cl Li Cl

Li

N

33c

Cl

Cl

FLi F F

Li

N N NF

COOH

COOH

NFHOOC F F

HOOC

N F

[a]

[b,c,d,e] [b,c] [b,a]

[f,g] [f] [f,h] [f,h]

(H3C)3Si

Scheme 23. Regiochemically exhaustive functionalization of 2-fluoropyridine. Reaction conditions: [a] LIDA in THF at –75 °C; [b] Cl2FCCClF2; [c] LiC4H9 in THF at –75 °C; [d] ClSi(CH3)3; [e] Excess LiC4H9 + LiOCH2CH2N(CH3)2 in hexanes at –75 °C; [f] (1.) CO2, (2.) aq. HCl; [g] (H9C4)4NF hydrate in THF at +25 °C; [h] HCOONH4 + cat. Pd/C in ethanol at +25 °C (stirred slurry).

14

Analogously, 3-fluoropyridine was converted through the organometallic intermediates

32c and 34a - c into the 3-fluoropyridine-2-, -4-, -5- and -6-carboxylic acids[58] (Scheme 24).

Chlorine and trimethylsilyl groups play again a crucial role in directing the metal to the

targeted spot. 4-Chloro-3-fluoropyridine features another impressive example of optionally

site selective metalation. LIDA in THF deprotonates the 5-position, but LITMP in (poorly

coordinating) DEE the 2-position. The latter outcome opens another entry to 3-fluoropyridine-

2-carboxylic acid.[58]

N N N

34c 34b 32c

Cl

F F F

Li

N

34a

F

Cl

LiLi

Li

N N N

F

COOH

NCOOHHOOC

HOOC

N

[a]

[b,e] [c,d] [b,a]

[f,h,g] [f,h] [f] [f,g]

F

FFF

(H3C)3Si (H3C)3Si

Scheme 24. Regiochemically exhaustive functionalization of 3-fluoropyridine. Reaction conditions: [a] LIDA in THF at –75 °C; [b] Cl2FCCClF2; [c] ClSi(CH3)3; [d] LITMP in THF at –75 °C; [e] Excess LiC4H9 + LiOCH2CH2N(CH3)2 in hexanes at –75 °C; [f] (1.) CO2, (2.) aq. HCl; [g] HCOONH4 + cat. Pd/C in methanol at +50 °C (stirred slurry); [h] (H9C4)4NF hydrate in THF at +25 °C.

2,4-Difluoropyridine[59] and 3,5-difluoropyridine[60] undergo metalation of course at the

location flanked by the two halogen atoms. 2,6-Difluoropyridine[61] and 3,4-

difluoropyridine[62] react with strong bases at, respectively, the 3- and 5-position, as expected.

The regioexhaustive functionalization of 2,3-difluoropyridine[63] is once more tributary to

the smart deployment of chlorine and trialkylsilyl protective groups followed by site-specific

metalation (intermediates 35a – c, Scheme 24), carboxylation and ultimate "makeup take off".

An alternative route to 5,6-difluoropyridine-3-carboxylic acid leads through 2,3-difluoro-4-

iodopyridine which is subjected to deprotonation-triggered heavy-halogen migration[14, 64]

prior to neutralization, iodine/lithium permutation and reaction with carbon dioxide.[57]

15

N N35c 35a

F F

Li

N35b

F

Cl

F

Li

N N

F

COOH

NF

HOOC

N

[a]

[c,d] [b,a]

[e,g] [e] [e,f]

F

FF

F

Li F F

HOOC F F

(H3C)3Si

Scheme 25. Regiochemically exhaustive functionalization of 2,3-difluoropyridine. Reaction conditions: [a] LIDA in THF at –75 °C; [b] Cl2FCCClF2; [c] ClSi(CH3)3; [d] Excess LiC4H9 + LiOCH2CH2N(CH3)2 in hexanes at –75 °C; [e] (1.) CO2, (2.) aq. HCl; [f] HCOONH4 + cat. Pd/C in ethanol at +25 °C (stirred slurry); [g] (H9C4)4NF hydrate in THF at +25 °C.

The same principles can be applied to 2,5-difluoropyridine.[57] The three possible

carboxylic acids are obtained via the intermediates 36a - c, Scheme 26). The 3,6-difluoro-

pyridinecarboxylic acid can be prepared either by exploiting the shielding effect of the

trimethylsilyl group (Scheme 26) or also by taking advantage of the ambivalent reactivity of

4-chloro-2,5-difluoropyridine which undergoes metalation with the superbasic LIC-KOR

mixture at the 3-position (as shown in Scheme 26), but with LITMP in diethyl ether (DEE) at

the 6-position.[57]

N N36c 36a

Li

N36b

K/Li

Cl

F

F

N N

COOH

NF

F

N

[a]

[d,e] [b,c]

[f,h] [f] [f,g]

(H3C)3Si

COOH

F

Li F F

HOOC F F

F

FF

F F

Scheme 26. Regiochemically exhaustive functionalization of 2,5-difluoropyridine. Reaction conditions: [a] LIDA in THF at –75 °C; [b] Cl2FCCClF2; [c] LIDA + N,N,N',N",N"-pentamethyldiethylenetriamine (PMDTA) + KOC(CH3)3 in THF at –75 °C; [d] ClSi(CH3)3; [e] LITMP in DEE at –75 °C; [f] (1.) CO2 (2.) aq. HCl; [g] Zn (powder) in 25% aq. NH3 at +25

16

°C (stirred slurry); [h] (H9C4)4NF hydrate in THF at +25 °C.

In the preceding four paragraphs several chlorofluoropyridylmetals are mentioned

which contain the two lightest halogen elements simultaneously and wherein the metal resides

at a chlorine-adjacent position (3-chloro-2-fluoropyrid-4-yllithium, 4,5-dichloro-6-

fluoropyrid-3-yllithium, 4-chloro-5-fluoropyrid-3-yllithium, 4-chloro-5,6-difluoropyrid-3-

yllithium and 4-chloro-2,6-difluoropyrid-3-ylpotassium/lithium). To this list 3,5-dichloro-2-

fluoropyrid-4-yllithium,[63] 5-chloro-2,3-difluoropyrid-4-yllithium[63] and 3-chloro-5-

fluoropyrid-4-yllithium[62] may be added.

The first three out of six possible trifluoropyridyllithiums have been described

recently: 4,5,6-trifluoropyrid-3-yllithium[62] (37b) and 2,4,6-trifluoropyrid-3-yllithium[59]

(37c). Two of the three possible tetrafluoropyridyllithiums are known: 2,3,4,6-

tetrafluoropyrid-3-yllithium[59,65] (38a) and 2,3,5,6-tetrafluoropyrid-4-yllithium[66] (38b)

(Scheme 27).

N N N

37a 37b 37c

N N

38a 38b

Li F Li

F

F

Li

F

FF

F

F

Li

F

F F F

F

F

F

Li

F

F

Scheme 27. A few tri- and tetrafluoro-pyridyllithiums.

Trifluoromethyl-substituted aromatic or heterocyclic building blocks attract more and

more attention.[67] The required starting material can be readily made either by treatment of a

trichloromethyl precursor with hydrogen fluoride,[68] a suitable carboxylic acid with sulfur

tetrafluoride[69] or by bromine or iodine displacement with in situ generated

trifluoromethylcopper.[70] If a metal can be selectively introduced into such a structure,

subsequent functionalization is a mere trifle.

Ten of twelve possible (trifluoromethyl)pyridyllithiums have been set free by

bromine/lithium or iodine/lithium permutation using butyllithium in tetrahydrofuran or

toluene.[71] They all proved chemically and thermally stable at temperatures around or below

–50 °C. Such species can also be generated by hydrogen/metal rather than halogen /metal

interconversion also the success of the metalation option depends closely on the exact

17

reaction conditions. 2-(Trifluoromethyl)pyrid-3-yllithium (39a, Scheme 28) is obtained

cleanly by treatment of 2-(trifluoromethyl)pyridine with LITMP in THF after 6 h.[72] After

short exposure times or in DEE inevitably regioisomeric mixtures are produced. Caubère's

base in DEE metalates 2-(trifluoromethyl)pyridine effectively at the 6-position (intermediate

39b).[72] 4-(Trifluoromethyl)pyridine can be smoothly lithiated with LITMP in THF at –75 °C

at the 3-position and with Caubère's base at the 2-position (intermediates 39c and 39d,

respectively, Scheme 28).

N N NCF3

Li Li

CF3

N

CF3

CF3Li Li

39a 39b 39c 39d

Scheme 28. Several (trifluoromethyl)pyridyl-lithiums from 2- and 4-(trifluoromethyl)pyridine by metalation (hydrogen/metal permutation).

According to a literature report,[73] not only 2,5-, 3,4- and 3,5-

bis(trifluoromethyl)pyridine but also 3-(trifluoromethyl)pyridine can be selectively metalated

at the 2- (or 6-)position and subsequently trapped as the carboxylic acids in satisfactory yields

(55 – 85%). The repetition of some parts of this work proved frustrating. The true yield of 3-

(trifluoromethyl)pyridine-2-carboxylic acid (via intermediate 40, Scheme 29) reproducibly

obtained by several collaborators was 1.0 – 1.5% rather than the claimed 75%. The main

component identified in the tar-like product mixture is 1-butyl-5-(difluoromethyl)pyridine,

obviously formed as a consequence of nucleophilic addition of the organometallic reagent to

the heterocyclic substrate (intermediate 41, Scheme 29).[72] 3-(Trifluoromethyl)-2-

(trimethylsilyl)pyridine can be isolated in 30% yield when generated under in situ trapping

conditions.[74] This compound can be readily converted by halodesilylation[75] into 2-bromo-

or 2-iodo-3-(trifluoromethyl)pyridine (X = Br, I) and, although not yet attempted, presumably

also by nitrodesilylation[76] into 2-nitro-3-(trifluoromethyl)pyridine (X = NO2) and by Hiyama

coupling[77] into 2-aryl-3-(trifluoromethyl)pyridines (X = aryl, Scheme 29).

18

N N

CF3 CF3

N

41 40

CF3

Li

[a or b][a]

HR Li

N

CF2

HR

N

CHF2

R

N

CF3

N

CF3

Si(CH3)3

X

[b]

[c]

[d]

N

CF3

COOH

[R = H9C4; X = Br, I, etc.]

Scheme 29. Reaction of 3-(trifluoromethyl)pyridine with strong bases: nucleophilic adition vs. deprotonation. Reaction conditions: [a] LiC4H9 in DEE at –75 °C. [b] LIDA and ClSi(CH3)3 in THF at –75 °C. [c] Heating with Br2 or ICl. [d] (1.) CO2 (2.) aq. HCl.

The metalation/functionalization sequence can also be applied to

(trifluoromethyl)pyridines carrying additional heterosubstituents. For example, when 2-

amino-3-chloro-5-(trifluoromethyl)pyridine was N-pivaloyl protected and subsequently

treated with two equivalents of LIDA, the resulting 4-lithiated intermediate (42, Scheme 30)

reacts with iodine or benzaldehyde and, after deprotection, affords the final products in

satisfactory over-all yield.[78]

N NNH

Cl Cl

Li

N

El

42

F3C F3C

N=C NH

ClF3C

[COR = COC(CH3)3; El = I, CH(OH)C6H5]

R

OLiRO O R

Scheme 30. Metalation and subsequent electrophilic substitution of N-pivaloyl protected 2-amino-3-chloro-5-(trifluoromethyl)pyridine.

The readily available[70,78-80] chloro(trifluoromethyl)pyridine are challenging model

compounds to test the scope of the methods elaborated for performing regiochemically

exhaustive functionalizations. In the entire series, one site is always kinetically more acidic

than the others and thus can be directly deprotonated. This is, for instance, the 4-position of 5-

chloro-2-(trifluoromethyl)pyridine.[80] The corresponding derivatives can be hence obtained

with minimal effort. The open question is whether or not the same set of organometallic

19

methods will routinely enable the preparation of the two other isomers. As the following

examples demonstrate, this is the case indeed.

Fast proton abstraction occurs again from the 4-position, when 2-chloro-5-

(trifluoromethyl)pyridine is treated with LIDA in the presence of lithium N,N-

diisopropylcarbamate and lithium bromide in THF at –75 °C.[79] Reaction of the intermediate

43 with elemental iodine provides 2-chloro-4-iodo-5-(trifluoromethyl)pyridine from which

the organometallic precursor species (43) can be regenerated by iodine/lithium permutation.

On the other hand, the iodo compound can be subjected to a LIDA-promoted heavy halogen

migration[64] which displaces the iodine from the 4- to the 6-position. Quenching of the

lithiated intermediate 44a produces a neutral 6-iodo compound which can be converted into

the corresponding carboxylic acid by halogen/metal permutation (intermediate 45a) and

subsequent carboxylation. Curiously, the iodine reappears at the 3- rather than at the 6-

position when its migration is triggered with the "slim" lithium piperidide (LIPIP) rather than

with the bulky LIDA. In this way, the 2-chloro-5-(trifluoromethyl)pyridine-3-carboxylic acid

can also be readily made (via intermediates 44b and 45b, Scheme 31).[79] 2-Chloro-5-

(trifluoromethyl)pyridine represents an atypical case as it covers the sole example of a

reagent-dependent directionally diverging heavy halogen migration known so far. In general,

protective groups are required to steer the metal to the targeted location.

N N

44a 43

Li

N

44b

Li

I

Cl

F3C

N N

I

NCl

F3C

N

[a]

[f] [b] [f]

I

I

Cl

Li Cl Cl

I Cl Cl

F3C

F3CF3C

F3C F3C

N N

Li

NCl

F3C

[g,h] [c] [g,h]

M

M Cl Cl

F3C F3C

45a 43 45b

N N

COOH

NCl

F3C

[i] [i] [i]

COOH

HOOC Cl Cl

F3C F3C

LiLi

[d] [e]

[M = Cl(I)Mg, Li]

20

Scheme 31. Regiochemically exhaustive functionalization of 2-chloro-5-(trifluoromethyl)pyridine. Reaction conditions: [a] LIDA + LiOOC-N(iC3H7)2 + LiBr in THF at –75 °C; [b] I2; [c] LiC4H9 in THF at –75 °C; [d] LIDA in THF at –75 °C; [e] LiN(CH2)5 (LIPIP) in THF at –75 °C (for 20 h); [f] rapid spontaneous swap of Li and I places; [g] H2O or HOCH3; [h] ClMgCH(CH3)2 (or LiC4H9) in THF at –75 °C; [i] (1.) CO2 (2.) aq. HCl.

3-Chloro-4-(trifluoromethyl)pyridine is cleanly metalated at the 2-position (intermediate

46, Scheme 32). Carboxylation leads to the corresponding carboxylic acid and condensation

with chlorotrimethylsilane to a 2-silylated derivative which undergoes metalation at the next

acidic 5-position (intermediate 47). Carboxylation gives the second acid whereas iodination

followed by deprotonation triggered heavy halogen migration,[64] neutralization and

iodine/magnesium permutation gives another organometallic intermediate (48)[79] which

opens the entry to the last missing carboxylic acid (Scheme 32).

N N46 47

CF3

N48

Cl

CF3

Li

N N

CF3

NCOOH

N

[a]

[g] [g,h] [g,i]

CF3

Cl

Si(CH3)3 Si(CH3)3

Li

HOOC

CF3CF3

[b,c]

Cl

CF3

Cl

Cl

Cl

Li

[d,a,e,f]

Cl

HOOC

Scheme 32. Regiochemically exhaustive functionalization of 3-chloro-4-(trifluoromethyl)-pyridine. Reaction conditions: [a] LITMP in DEE at –100 °C; [b] ClSi(CH3)3; [c] LITMP in THF at –75 °C; [d] I2; [e] H2O or HOCH3 or acid; [f] LiC4H9 in toluene at –75 °C; [g] (1.) CO2 (2.) aq. HCl; [h] (1.) aq. sodium hydroxide at 100 °C (2.) aq. HCl; [i] (H9C4)4NF hydrate in refluxing THF.

Alkyllithium or lithium dialkylamide bases attack 3-chloro-2-(trifluoromethyl)pyridine at

the 4-position, as expected. Iodination of the intermediate 49a followed by deprotonation-

triggered heavy halogen migration, neutralization and iodine/metal permutation (using

isopropylmagnesium chloride) produces an organometallic species 49b. Caubère's base

21

metalates 3-chloro-2-(trifluoromethyl)pyridine at the 6- (rather than the 4-)position, thus

giving rise to species 49c. Standard carboxylation and ultimate neutralization transforms the

intermediates 49 into the three corresponding pyridinecarboxylic acids (Scheme 33).[78]

N N

49c 49a

M

N

49b

Cl

CF3

N N

COOH

NCF3

N

[a]

[e] [e] [e]

Cl

CF3 CF3

Cl

Cl

Cl

Cl[b,a,c,d]

Cl

CF3

M

HOOC

M

CF3

HOOC

CF3

[M = Li or MgCl(I)]

Scheme 33. Regiochemically exhaustive functionalization of 3-chloro-2-(trifluoromethyl)-pyridine. Reaction conditions: [a] LIDA in THF at –75 °C; [b] I2; [c] HOCH3; [d] ClMgCH(CH3)2 in THF at 0 °C; [e] (1.) CO2 (2.) aq. HCl.

2-Chloro-6-(trifluoromethyl)pyridine itself undergoes metalation at the 3-position

(intermediate 50, Scheme 34) but at the 5-position (intermediate 51), when the 3-position is

occupied by a trialkylsilyl protective group. The third precursor to the targeted

pyridinecarboxylic acids is obtained after lithiation and iodination at the 3-position by

deprotonation-triggered displacement of the heavy halogen atom to the 4-position in exchange

against lithium (intermediate 53) followed by neutralization and halogen/metal permutation

using lithium tributylmagnesate[81] (Scheme 34).[79]

N N

51 50

N

52

Li

I

Cl

N N NCl

N

[a]

[b,c] [d,e]

[f,g] [f] [h,i,f]

Cl

F3C Cl Cl

F3C Cl Cl

Li

HOOC

F3C

Li

F3C F3C

COOH

F3C

COOH

F3C

Si(CH3)3

22

Scheme 34. Regioexhaustive functionalization of 2-chloro-6-(trifluoromethyl)pyridine. Reaction conditions: [a] LIDA in THF at –85(!) °C; [b] ClSi(CH3)3; [c] LITMP in THF at –75 °C; [d] I2; [e] LIDA in THF at –75 °C; [f] (1.) CO2 (2.) aq. HCl; [g] (H9C4)4NF hydrate in THF at +25 °C; [h] H2O or HOCH3 or acid; [i] LiMg(C4H9)3 (0.33 molar equivalents).

The regioexhaustive functionalization of 2-bromo-6-(trifluoromethyl)pyridine passes

through virtually the same steps (Scheme 35). Direct metalation affects the 3-position but is,

by silylation there, deflected to the 5-position (intermediates 53 and 54, Scheme 34).

Introduction of an iodine atom at the 3-position and its basicity gradient-driven migration to

the adjacent 4-position generates intermediate 55. When the 2-bromo-4-iodo-6-

(trifluoromethyl)pyridine formed upon neutralization is treated with isopropylmagnesium

chloride in THF at 0 °C, whereas the iodine atom is replaced by the metal the bromine atom is

completely retained. This comparison reveals a marked discrimination of the halogen/metal

permutation reaction in favor of the heaviest halogen. Iodine participates instantaneously in

this process, bromine more slowly and chlorine, not to speak of fluorine, not at all.

N N

54 53

N

55

Li

I

Br

N N NBr

N

[a]

[b,c] [d,e]

[f,g] [f] [h,i,f]

Br

F3C Br Br

F3C Br Br

Li

HOOC

F3C

Li

F3C F3C

COOH

F3C

COOH

F3C

Si(CH3)3

Scheme 35. Regioexhaustive functionalization of 2-bromo-6-(trifluoromethyl)pyridine. Reaction conditions: [a] LIDA in THF at –85(!) °C; [b] ClSi(CH3)3; [c] LITMP in THF at –75 °C; [d] I2; [e] LIDA in THF at –75 °C; [f] (1.) CO2 (2.) aq. HCl; [g] (H9C4)4NF hydrate in refluxing THF; [h] H2O or HOCH3 or acid; [i] ClMgCH(CH3)2 in THF at 0 °C.

The last examples featuring halo(trifluoromethyl)pyridines (Schemes 31 – 35)

demonstrate the general feasibility of regioselective functionalizations by means of the

"toolbox methods".[12] At the same time, one recognizes the remarkable thermal stability

23

conferred upon pyridyllithiums by the trifluoromethyl group and an additional halogen

substituent. Thus, neither 2-bromo-4-(trifluoromethyl)pyrid-3-yllithium (56a) nor 5-bromo-2-

(trifluoromethyl)pyrid-4-yllithium (56b) and not even 2-iodo-4-(trifluoromethyl)pyrid-3-

yllithium (57a) nor 4-iodo-2-(trifluoromethyl)pyrid-3-yllithium (57b) are prone to the -

elimination of, respectively, lithium bromide or lithium iodide when kept at –75 °C for

prolonged periods of time.

3. Summary and Outlook

The methods outlined above enable the effortless and regiochemically exhaustive

functionalization of heterosubstituted pyridines (Scheme 36) and hence open an entry to a

great variety of attractive building blocks for research and development in the life sciences

arena. This potential is particularly appealing when fluorine-bearing pyridine derivatives are

targeted as the smallest halogen is a unique tool to engineer and fine-tune biological

properties.[81]

N

X

N

X

N

X

N

X

N

X

El

ElEl

El

Scheme 36. Regiochemically exhaustive substitution of, for example, a 3-heterosubstituted pyridine.

Despite all the impressive applications so far featured, we should not ignore inherent

problems. The metalation of pyridines is a tightrope walk. Pyridine is more acidic than

benzene by 10 kcal/mol in the gas phase[82] and, based on rate estimates regarding the base-

catalyzed hydrogen isotope exchange, by some 7.6 kcal/mol in the condensed phase[83, 84]. The

kinetics reflect such differences in thermodynamics. 2-Fluoropyridine is metalated by sec-

butyllithium or LITMP in tetrahydrofuran at –75 °C, after statistical correction, 720 or,

respectively, 520 times faster than benzene[85]. At the same time the proneness of the substrate

to undergo nucleophilic additions or substitutions increases steeply when a benzenic

derivative is replaced by a pyridinic one. It requires skills and cleverly selected working

conditions to maneuver successfully between the desired and undesired reaction mode.

24

If adequate precautions are taken, the organometallic approach to structure elaboration

offers singular advantages. The possibility to attach substituents, in particular functionality,

selectively to any vacant position ("regiochemical exhaustiveness"[12, 56]) has already been

mentioned above. Product flexibility is another inestimable virtue. The metal present in the

reaction intermediate may be replaced by any electrophilic component, carbon dioxide, the

popular trapping agent, being just one out of hundreds if not thousands of candidates. Finally,

organometallic reactions use to proceed rapidly and often quantitatively. This is an invitation

to realize shortcuts in synthesis sequences and to contract several individual steps to a one-pot

protocol.[86]

Traditionally pyridines play a privileged role in the realm of heterocycles. Therefore, they

were in the focus of the present article. However, the concepts and methods described can be

of course applied to other six- or five-membered N-heterocycles or O- and S-heterocycles as

well.

Acknowledgment

Financial support was provided by the Schweizerische Nationalfonds zur Förderung

der wissenschaftlichen Forschung (grant 20-63'584-00), the Bundesamt für Berufsbildung und

Technologie (KTI-Projekt 5474.1 KTS) and the Bundesamt für Bildung und Wissenschaft

(grant 97.0083 linked to the TMR project FMRXCT-970129; grant C02.0060 linked to a

COST D24 project).

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25

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